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European Journal of Human Genetics: EJHG

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https://www.readbyqxmd.com/read/28875981/unraveling-genetic-predisposition-to-familial-or-early-onset-gastric-cancer-using-germline-whole-exome-sequencing
#1
Ingrid P Vogelaar, Rachel S van der Post, J Han Jm van Krieken, Liesbeth Spruijt, Wendy Ag van Zelst-Stams, C Marleen Kets, Jan Lubinski, Anna Jakubowska, Urszula Teodorczyk, Cora M Aalfs, Liselotte P van Hest, Hugo Pinheiro, Carla Oliveira, Shalini N Jhangiani, Donna M Muzny, Richard A Gibbs, James R Lupski, Joep de Ligt, Lisenka E L M Vissers, Alexander Hoischen, Christian Gilissen, Maartje van de Vorst, Jelle J Goeman, Hans K Schackert, Guglielmina N Ranzani, Valeria Molinaro, Encarna B Gómez García, Frederik J Hes, Elke Holinski-Feder, Maurizio Genuardi, Margreet G E M Ausems, Rolf H Sijmons, Anja Wagner, Lizet E van der Kolk, Inga Bjørnevoll, Hildegunn Høberg-Vetti, Ad Geurts van Kessel, Roland P Kuiper, Marjolijn J L Ligtenberg, Nicoline Hoogerbrugge
Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70...
September 6, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28875980/autosomal-recessive-congenital-ichthyosis-cers3-mutations-identified-by-a-next-generation-sequencing-panel-targeting-ichthyosis-genes
#2
Leila Youssefian, Hassan Vahidnezhad, Amir Hossein Saeidian, Soheila Sotoudeh, Hamidreza Mahmoudi, Maryam Daneshpazhooh, Nessa Aghazadeh, Rebecca Adams, Alireza Ghanadan, Sirous Zeinali, Paolo Fortina, Jouni Uitto
There are at least 38 mutant genes known to be associated with the ichthyosis phenotypes, and autosomal recessive congenital ichthyosis (ARCI) is a specific subgroup caused by mutations in 13 different genes. Mutations in some of these genes, such as CERS3 with only two previous reports, are rare. In this study, we identified mutations in candidate genes in consanguineous families with ARCI with a next generation sequencing (NGS) array that incorporates 38 ichthyosis associated genes. We applied this sequencing array to DNA from 140 ichthyosis families with high prevalence of consanguinity...
September 6, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28853723/ndufaf4-variants-are-associated-with-leigh-syndrome-and-cause-a-specific-mitochondrial-complex-i-assembly-defect
#3
Fabian Baertling, Laura Sánchez-Caballero, Mariël A M van den Brand, Liesbeth T Wintjes, Maaike Brink, Frans A van den Brandt, Callum Wilson, Richard J T Rodenburg, Leo G J Nijtmans
Mitochondrial respiratory chain complex I consists of 44 different subunits and can be subgrouped into three functional modules: the Q-, the P- and the N-module. NDUFAF4 (C6ORF66) is an assembly factor of complex I that associates with assembly intermediates of the Q-module. Via exome sequencing, we identified a homozygous missense variant in a complex I-deficient patient with Leigh syndrome. Supercomplex analysis in patient fibroblasts revealed specifically altered stoichiometry. Detailed assembly analysis of complex I, indicative of all of its assembly routes, showed an accumulation of parts of the P- and the N-module but not the Q-module...
August 30, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28853722/propionic-acidemia-as-a-cause-of-adult-onset-dilated-cardiomyopathy
#4
Moniek Riemersma, Mark R Hazebroek, Appolonia T J M Helderman-van den Enden, Gajja S Salomons, Sacha Ferdinandusse, Martijn C G J Brouwers, Liesbeth van der Ploeg, Stephane Heymans, Jan F C Glatz, Arthur van den Wijngaard, Ingrid P C Krapels, Jörgen Bierau, Han G Brunner
Dilated cardiomyopathy (DCM) is extremely heterogeneous with a large proportion due to dominantly inherited disease-causing variants in sarcomeric genes. Recessive metabolic diseases may cause DCM, usually with onset in childhood, and in the context of systemic disease. Whether metabolic defects can also cause adult-onset DCM is currently unknown. Therefore, we performed an extensive metabolic screening in 36 consecutive adult-onset DCM patients. Diagnoses were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA)...
August 30, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28853721/the-wide-spectrum-of-pot1-gene-variants-correlates-with-multiple-cancer-types
#5
Oriol Calvete, Pablo Garcia-Pavia, Fernando Domínguez, Gaelle Bougeard, Kristin Kunze, Andreas Braeuninger, Alex Teule, Adriana Lasa, Teresa Ramón Y Cajal, Gemma Llort, Victoria Fernández, Conxi Lázaro, Miguel Urioste, Javier Benitez
The POT1 protein binds and protects telomeres. Germline variants in the POT1 gene have recently been shown to be associated with risk of developing tumors in different tissues such as familial chronic lymphocytic leukemia, colorectal, glioma and melanoma tumors. Recently, we uncovered a variant in the POT1 gene (p.R117C) as causative of familial cardiac angiosarcomas (CAS) in Li-Fraumeni-like (LFL) syndrome families. Our in silico studies predicted that this protein had lost the ability to interact with TPP1 and single-stranded DNA...
August 30, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28853720/the-y-chromosome-a-blueprint-for-men-s-health
#6
REVIEW
Akhlaq A Maan, James Eales, Artur Akbarov, Joshua Rowland, Xiaoguang Xu, Mark A Jobling, Fadi J Charchar, Maciej Tomaszewski
The Y chromosome has long been considered a 'genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component...
August 30, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28853719/viewing-the-male-specific-chromosome-y-in-a-fresh-new-light
#7
Christian F Deschepper
No abstract text is available yet for this article.
August 30, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28853718/genetic-correlations-between-intraocular-pressure-blood-pressure-and-primary-open-angle-glaucoma-a-multi-cohort-analysis
#8
Hugues Aschard, Jae H Kang, Adriana I Iglesias, Pirro Hysi, Jessica N Cooke Bailey, Anthony P Khawaja, R Rand Allingham, Allison Ashley-Koch, Richard K Lee, Sayoko E Moroi, Murray H Brilliant, Gadi Wollstein, Joel S Schuman, John H Fingert, Donald L Budenz, Tony Realini, Terry Gaasterland, William K Scott, Kuldev Singh, Arthur J Sit, Robert P Igo, Yeunjoo E Song, Lisa Hark, Robert Ritch, Douglas J Rhee, Vikas Gulati, Shane Haven, Douglas Vollrath, Donald J Zack, Felipe Medeiros, Robert N Weinreb, Ching-Yu Cheng, Daniel I Chasman, William G Christen, Margaret A Pericak-Vance, Yutao Liu, Peter Kraft, Julia E Richards, Bernard A Rosner, Michael A Hauser, Caroline C W Klaver, Cornelia M vanDuijn, Jonathan Haines, Janey L Wiggs, Louis R Pasquale
Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively...
August 30, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28832570/accurate-and-comprehensive-analysis-of-single-nucleotide-variants-and-large-deletions-of-the-human-mitochondrial-genome-in-dna-and-single-cells
#9
Filippo Zambelli, Kim Vancampenhout, Dorien Daneels, Daniel Brown, Joke Mertens, Sonia Van Dooren, Ben Caljon, Luca Gianaroli, Karen Sermon, Thierry Voet, Sara Seneca, Claudia Spits
Massive parallel sequencing (MPS) can accurately quantify mitochondrial DNA (mtDNA) single nucleotide variants (SNVs), but no MPS methods are currently validated to simultaneously and accurately establish the breakpoints and frequency of large deletions at low heteroplasmic loads. Here we present the thorough validation of an MPS protocol to quantify the load of very low frequency, large mtDNA deletions in bulk DNA and single cells, along with SNV calling by standard methods. We used a set of well-characterized DNA samples, DNA mixes and single cells to thoroughly control the study...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28832569/swegen-a-whole-genome-data-resource-of-genetic-variability-in-a-cross-section-of-the-swedish-population
#10
Adam Ameur, Johan Dahlberg, Pall Olason, Francesco Vezzi, Robert Karlsson, Marcel Martin, Johan Viklund, Andreas Kusalananda Kähäri, Pär Lundin, Huiwen Che, Jessada Thutkawkorapin, Jesper Eisfeldt, Samuel Lampa, Mats Dahlberg, Jonas Hagberg, Niclas Jareborg, Ulrika Liljedahl, Inger Jonasson, Åsa Johansson, Lars Feuk, Joakim Lundeberg, Ann-Christine Syvänen, Sverker Lundin, Daniel Nilsson, Björn Nystedt, Patrik Ke Magnusson, Ulf Gyllensten
Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28832568/uptake-of-genetic-testing-by-the-children-of-lynch-syndrome-variant-carriers-across-three-generations
#11
Toni T Seppälä, Kirsi Pylvänäinen, Jukka-Pekka Mecklin
Many Lynch syndrome (LS) carriers remain unidentified, thus missing early cancer detection and prevention opportunities. Tested probands should inform their relatives about cancer risk and options for genetic counselling and predictive gene testing, but many fail to undergo testing. To assess predictive testing uptake and demographic factors influencing this decision in LS families, a cross-sectional registry-based cohort study utilizing the Finnish Lynch syndrome registry was undertaken. Tested LS variant probands (1184) had 2068 children divided among three generations: 660 parents and 1324 children (first), 445 and 667 (second), and 79 and 77 (third)...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28832567/third-party-interpretation-of-raw-genetic-data-an-ethical-exploration
#12
REVIEW
Lauren Badalato, Louiza Kalokairinou, Pascal Borry
In the wake of recent regulations targeting direct-to-consumer genetic testing (DTC-GT), an increasing number of websites have emerged that offer consumers alternative means to derive health information from their DTC-GT raw data. While the ethical concerns associated with DTC-GT have been extensively discussed in the literature, the implications of third party interpretation (TPI) websites have remained largely unexplored. Here we sought to describe these services and elucidate their ethical implications in the context of the current DTC-GT debate...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28832565/massive-sequencing-of-70-genes-reveals-a-myriad-of-missing-genes-or-mechanisms-to-be-uncovered-in-hereditary-spastic-paraplegias
#13
Sara Morais, Laure Raymond, Mathilde Mairey, Paula Coutinho, Eva Brandão, Paula Ribeiro, José Leal Loureiro, Jorge Sequeiros, Alexis Brice, Isabel Alonso, Giovanni Stevanin
Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (>60 causative genes), 40-70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28832564/haplotype-based-stratification-of-huntington-s-disease
#14
Michael J Chao, Tammy Gillis, Ranjit S Atwal, Jayalakshmi Srinidhi Mysore, Jamshid Arjomand, Denise Harold, Peter Holmans, Lesley Jones, Michael Orth, Richard H Myers, Seung Kwak, Vanessa C Wheeler, Marcy E MacDonald, James F Gusella, Jong-Min Lee
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28832562/a-clinically-driven-variant-prioritization-framework-outperforms-purely-computational-approaches-for-the-diagnostic-analysis-of-singleton-wes-data
#15
Zornitza Stark, Harriet Dashnow, Sebastian Lunke, Tiong Y Tan, Alison Yeung, Simon Sadedin, Natalie Thorne, Ivan Macciocca, Clara Gaff, Alicia Oshlack, Susan M White, Paul A James
Rapid identification of clinically significant variants is key to the successful application of next generation sequencing technologies in clinical practice. The Melbourne Genomics Health Alliance (MGHA) variant prioritization framework employs a gene prioritization index based on clinician-generated a priori gene lists, and a variant prioritization index (VPI) based on rarity, conservation and protein effect. We used data from 80 patients who underwent singleton whole exome sequencing (WES) to test the ability of the framework to rank causative variants highly, and compared it against the performance of other gene and variant prioritization tools...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28812650/autosomal-recessive-cone-rod-dystrophy-can-be-caused-by-mutations-in-the-atf6-gene
#16
Anna Skorczyk-Werner, Wei-Chieh Chiang, Anna Wawrocka, Katarzyna Wicher, Małgorzata Jarmuż-Szymczak, Magdalena Kostrzewska-Poczekaj, Aleksander Jamsheer, Rafał Płoski, Małgorzata Rydzanicz, Dorota Pojda-Wilczek, Nicole Weisschuh, Bernd Wissinger, Susanne Kohl, Jonathan H Lin, Maciej R Krawczyński
Inherited retinal dystrophies (IRDs) are clinically and genetically highly heterogeneous, making clinical diagnosis difficult. The advances in high-throughput sequencing (ie, panel, exome and genome sequencing) have proven highly effective on defining the molecular basis of these disorders by identifying the underlying variants in the respective gene. Here we report two siblings affected by an IRD phenotype and a novel homozygous c.1691A>G (p.(Asp564Gly)) ATF6 (activating transcription factor 6A) missense substitution identified by whole exome sequencing analysis...
August 16, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28792001/implicating-candidate-genes-at-gwas-signals-by-leveraging-topologically-associating-domains
#17
Gregory P Way, Daniel W Youngstrom, Kurt D Hankenson, Casey S Greene, Struan Fa Grant
Genome-wide association studies (GWAS) have contributed significantly to the understanding of complex disease genetics. However, GWAS only report association signals and do not necessarily identify culprit genes. As most signals occur in non-coding regions of the genome, it is often challenging to assign genomic variants to the underlying causal mechanism(s). Topologically associating domains (TADs) are primarily cell-type-independent genomic regions that define interactome boundaries and can aid in the designation of limits within which an association most likely impacts gene function...
August 9, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28905884/clinical-utility-gene-card-for-hereditary-angioedema-with-normal-c1-inhibitor-haenc1
#18
Christiane Stieber, Sven Cichon, Markus Magerl, Markus M Nöthen
No abstract text is available yet for this article.
October 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28905883/acceptable-applications-of-preimplantation-genetic-diagnosis-pgd-among-israeli-pgd-users
#19
Shachar Zuckerman, David A Zeevi, Sigal Gooldin, Gheona Altarescu
The use of PGD technology to select against genetic disorders and traits is increasing. Although PGD may eliminate some of the obstacles related to conservative options of prenatal diagnosis, it can raise personal, social and moral questions. Ethical issues concerning the justified uses of PGD are a subject of ongoing debate among medical and bioethical communities. Although attitudes toward the acceptable uses of PGD were evaluated among population groups worldwide, bioethics councils were criticized for ignoring public perspectives...
October 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28905882/identification-of-causative-variants-in-txnl4a-in-burn-mckeown-syndrome-and-isolated-choanal-atresia
#20
Jacqueline A C Goos, Sigrid M A Swagemakers, Stephen R F Twigg, Marieke F van Dooren, A Jeannette M Hoogeboom, Christian Beetz, Sven Günther, Frank J Magielsen, Charlotte W Ockeloen, Maria A Ramos-Arroyo, Rolph Pfundt, Helger G Yntema, Peter J van der Spek, Philip Stanier, Dagmar Wieczorek, Andrew O M Wilkie, Ans M W van den Ouweland, Irene M J Mathijssen, Jane A Hurst
Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p...
October 2017: European Journal of Human Genetics: EJHG
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